Pyruvate Carboxylase Deficiency

PROTOCOL 18 Pyruvate Carboxylase Deficiency
Nutrition Support of Infants and Children With

PROVIMIN Protein-Vitamin-Mineral Formula Component With Iron
I.
Introduction
Pyruvate can be converted to phosphoenolpyruvate (PEP), oxaloacetate (OAA), acetyl-CoA (AcCoA),
alanine, or lactate. The enzymes involved are pyruvate kinase (PK), phosphoenolpyruvate
carboxykinase (PEPCK), pyruvate dehydrogenase (PDH), pyruvate carboxylase (PC), alanine
aminotransferase (AAT), and lactate dehydrogenase (LDH) (10, 32).
LDH
Carbohydrate
Pyruvate*
Lactate*
AAT
Glucose
PK
PDH,
Thiamin
PC
Biotin
Alanine*
AcCoA
PEP
PEPCK
OAA
Fatty Acids
Aspartate
Site of enzyme malfunction

* Accumulates in untreated PC deficiency
Figure Q. Metabolic fates of pyruvate (modified from reference 32)

PC, a biotin-requiring enzyme, is located in the mitochondrial matrix where it catalyzes the first
step in gluconeogenesis and supplies OAA from pyruvate. OAA is in equilibrium with aspartate. PC
deficiency may result from biotinidase deficiency or from a structural change in the PC apoprotein (10,
32).
Aspartic acid, made from OAA, or used to synthesize OAA, may become deficient in severe PC
deficiency. With depletion of aspartate, the urea cycle does not function normally and citrullinemia,
hyperammonemia, and hyperlysinemia result. Aspartate is important in the shuttle mechanism that
transfers reducing equivalents across the mitochondrial membrane. Inadequate concentrations of
aspartate in the cytosol result in an increase in the lactate/pyruvate ratio (9, 10, 32).
Clinical symptoms of PC deficiency are heterogeneous ranging from a severe infantile (A and B)
type to a benign variant (C) (3, 17, 18, 33, 45).
II.
Outcome of Nutrition Support

Patients with no PC apoenzyme activity often die in infancy. Patients with milder forms of PC
deficiency (> 10% activity) treated with a moderate carbohydrate and protein and low-fat diet
supplemented with citrate, glutamine (GLUNH2), aspartate, asparagine (ASPNH2), and thiamin have
had good outcomes (4, 17, 33, 39, 45).
III.
Establish Diagnosis
A. The Defect
1. Defective functioning of PC results from defective PC apoenzyme, biotinidase deficiency, or
absence of an inhibitor of TPP-ATP phosphoryltransferase (40).
2001 Ross Products Division
Pyruvate Carboxylase Deficiency 325
B. Clinical Evaluation
1. Any infant or child who presents with the following symptoms should be evaluated for PC
deficiency:
a. Clinical:
1) Anorexia, irritability, lethargy, delayed neurologic development, coma, mental
retardation, hepatomegaly, hypotonia (4, 8, 15, 16, 30, 32).
b. Laboratory:
1) Metabolic acidosis; -ketoglutarate in urine; elevated lactate/pyruvate ratio;
elevated lactate and pyruvate; elevated acetoacetate/-hydroxybutyrate ratio;
elevated blood ammonia; hypoglycemia; elevated plasma alaniSne (ALA),
citrulline (CIT) (9), lysine (LYS), proline (PRO), absent or decreased PC activity in
cultured skin fibroblasts, leukocytes or hepatocytes.
2. Prenatal diagnosis may be made by measuring PC activity in amniocytes and chorionic villus
cells (4, 6, 8, 12, 14-16, 20, 25, 32).
3. See references 2, 3, 8, 27, 32, 34, 40, 44, and 46 for methods of diagnosis.
IV.
Rationale for Nutrition Support

A. Correct Primary Imbalance in Metabolic Relationships
1. Provide energy from major nutrients as follows: 15% protein, 50% carbohydrate, 35% fat.
2. Administer sodium bicarbonate as needed to maintain normal acid-base status (2, 7, 10, 19).
B. Stimulate Pyruvate Dehydrogenase Activity.
1. Supplement with oral thiamin (5, 7, 19, 20).
C. Supply Product of Blocked Primary Pathway
1. Supplement with precursors of OAA; ASP, citric acid, GLUNH2 (2, 4, 5, 21, 28).
V.
Establish Goals of Nutrition Support

A. Maintain Following Analytes in Plasma in Ranges Noted or in Normal Range for Age Established
by Laboratory Used:
Analyte
Acetoacetate
-Hydroxybutyrate
Citric acid
Glucose
Lactate
Pyruvate
Ammonia
0.03 - 0.30 mmol/L

< 0.100 mmol/L
0.060 - 0.160 mmol/L
3.9 - 6.1 mmol/L
0.5 - 2.0 mmol/L (37)
0.035 - 0.100 mmol/L (37)
0 - 35 mol/L (37)
B. Maintain Following Plasma Amino Acids and Glucose in Ranges Noted or in Normal Range for
Age Established by Laboratory Used:
Amino Acid (37)
Alanine
Arginine
Aspartate
CIT
Glutamine
LYS
PRO
(mol/L)
163- 653
34 - 140
1 -25
1 - 55
250 - 823
50 - 254
50 - 273
Growth, Development, and Nutrition Status

1. Support normal growth rate in infants and children.
2. Support normal development.
3. Maintain normal nutrition status.
a. Prevent catabolism.
326 Pyruvate Carboxylase Deficiency
b. Avoid prolonged fasting.
VI.
Establish Prescription
A. Energy
1. Prescribe amount that should support normal weight gain for infants and children and maintain
appropriate weight for height in adults (Table 18-1, p 332).
2. Requirements vary widely.
3. For infants who sleep more than 4 hours at night, add uncooked Argo cornstarch (2 g/kg
body weight) to last feed at night (43).
Warning:
Inadequate energy intake will result in growth failure (22).
B. Fat (22)
1. Prescribe amount of total fat that promotes goals of nutrition support.
a. Supply about 35% of total daily energy as fat (11).
1) Prescribe 3% of total energy as linoleic acid and 1.0% as -linolenic acid.
Warning:
Essential fatty acid deficiency may occur if intakes of linoleic acid and
-linolenic acid are inadequate.
C. Protein
1. Prescribe amount that supplies about 15% of total energy for infants (Table 18-1, p 332).
D. Carbohydrate
1. Prescribe remaining energy as carbohydrate.
E. Thiamin (15, 16 19, 24, 31, 42)
1. Supplement diet with 32-64 mg/kg of thiamin daily.
F. Citric Acid, L-Arginine, L-ASPNH2, L-ASP , L-GLUNH2 (15, 21, 28, 29, 31, 41)
1. Supplement diet with any or all nutrients listed in F required to maintain plasma citrate
concentrations in normal range.
2. Supplement with citrate daily (up to 7.5 mmol/kg/day, part as sodium and part as potassium
salt) (1) to maintain normal plasma citrate and OAA concentrations.
3. Supplement with following amounts of L-amino acids daily, if required. Modify based on
plasma concentrations.
L-Arginine
L-Asparagine
L-Aspartic acid
L-Glutamic acid
L-Glutamine
To maintain normal plasma concentration

68 mg/kg
18 - 360 mg/kg
52 mg/kg
460 mg/kg
G. Biotin Has Not Proven To Be of Benefit in Patients With No PC Activity (35).

H. Fluid
1. Prescribe amount that will supply water requirements (Table 18-1, p 332). Under normal
circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL to children and adults
for each kcal ingested.
2. Requirements may be higher than recommended secondary to accompanying fever.
I.
Fasting
1. Instruct parents and/or caretakers to prevent infants from fasting > 4 hours, children > 6 hours,
and adults > 8 hours.
VII. Fill Prescription

A. Fat
1. Determine amount of infant formula with iron, beikost, or table foods (Tables 18-2, p 332, and
18-3, p 333) required to supply about 35% of energy prescription as fat.
B. Protein
1. Calculate grams of protein required to provide about 15% of energy prescription.
2. Determine protein provided by infant formula with iron, beikost, or table foods (Tables 18-2
and 18-3, pp 332 and 333) required to supply fat prescription.
3. Subtract amount determined above from total protein prescription (Table 18-2, p 332).
4. Supply any remaining prescribed protein with ProViMin (Table 6-4, p 118), skim milk
(Appendix 8, A-8), or other fat-free or low-fat protein sources (Table 18-3, p 333).
C. Energy
1. Calculate energy supplied by infant formula with iron (until 1st birthday), beikost, or table
foods required to supply fat and that supplied by ProViMin (Table 18-2, p 332), skim milk
(Appendix 8, A-8), and other protein-containing foods (Table 18-2, p 332).
2. Subtract amount determined above from total energy prescription.
a. Use infant formula with iron until 2nd birthday to help supply needed iron.
3. Supply remaining prescribed energy with Polycose Glucose Polymers powder (23 kcal/Tbsp,
3.8 kcal/g) or liquid (2 kcal/mL) (Appendix 9, p A-9), sugar (48 kcal/Tbsp), beikost, or table
foods containing little or no fat (Tables 18-2 and 18-3 pp 332 and 333).
a. Do not use corn syrup or table sugar for infants because of osmolarity they yield (26).
b. Do not use honey for infants because it may contain botulinum toxin (38).
4. Add beikost or table foods after infant is 3 to 4 months old or is developmentally ready to
provide variety in taste, color, and texture (Table 18-2, p 332).
D. Fluid and Mixing Instructions
1. Boil bottles, nipples, rings and mixing utensils for 5 minutes and cool. Boil more water for
5 minutes and cool to room temperature.
2. Measure or weigh specified amounts of boiled, cooled water; infant formula; ProViMin;
carbohydrate; citric acid; and L-amino acids into clean containers.
3. Pour 1/2 of specified amount of boiled, cooled water into clean blender. Running blender at
slow speed, gradually add ProViMin and blend mixture for at least 15 seconds.
4. Slowly pour specified amount of infant formula, citric acid, and L-amino acids into blender and
continue blending for no longer than 1 to 3 seconds.
5. Dissolve powdered carbohydrate in some of remaining water and pour into ProViMin mixture,
mix well, add water to yield prescribed volume and pour into opaque sterilized nursing bottles
or cups. Prepared formula not used immediately should be refrigerated and used within
24 hours. Shake well before feeding.
6. Do not use microwave oven to warm formula. Unevenly heated formula can burn infants and
steam can make bottles explode.
7. Discard formula remaining in bottle or cup after feeding.
8. Store unopened cans at room temperature. Cover opened can and store in dry place (not in
refrigerator). Use within 1 month after opening.
9. Notify parents or caretakers when they may discontinue aseptic technique in making formula.
E. Diet Guide
1. Provide parents, caretakers, or patient with completed Diet Guide (Table 18-4, p 335) with
each diet change.
2. If necessary, use uncooked Argo cornstarch (2 g/kg body weight, 1:2 ratio cornstarch to water)
in daytime feeds to prevent hypoglycemia (43).
Warning:
Never permit patient to fast > 4 hours if an infant, > 6 hours if child, and less
time if patient is febrile, has diarrhea, or is vomiting.
VIII. Evaluate Adequacy and Safety of Planned Nutrition Support

A. Nutrient Adequacy
1. Determine if diet provides nutrients in amounts prescribed in Section VI, Establish
Prescription, p 327.
a. See Table 18-2, p 332, for composition ProViMin, skim milk, and infant formulas with iron.
b. See Appendix 9, p A-9, for composition of Polycose.
2. Check diet to determine if it supplies Recommended Dietary Intakes (RDIs) for minerals and
vitamins (Table 6-4, p 118 and Appendices 13 and 14, pp A-14 and A-15).
a. See Appendices 4 through 7, pp A-4 to A-7, for complete nutrient composition of infant
formulas.
b. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is
not available.
c. If ProViMin mixture provides < 100% of RDIs for infants and < 75% for children and
adults, supplement diet with needed minerals and vitamins if not provided by beikost or
table foods and laboratory tests indicate need (Appendix 11, p A-10, for composition of
supplements).
B. Osmolarity
1. If concentration of prescribed medical food mixture is > 27 kcal/fl oz, determine if osmolarity
is in acceptable range.
a. Determine osmolarity by laboratory analysis or use mathematical formula given in
Appendix 18, p A-20.
b. Osmolarity per gram of ProViMin powder is 2.74 mosm.
2. If osmolarity is > 450 mosm/L for infants (23), > 750 mosm/L for children, > 1,000 mosm/L for
adults, or is greater than tolerated by patient, increase water content of prescribed medical
food mixture and recalculate its osmolarity (26).
C. Potential Renal Solute Load
1. Dehydration will result if renal solute load is greater than renal-concentrating ability of patient.
2. If concentration of medical food mixture prescribed is > 27 kcal/fl oz, estimate its potential
renal solute load.
a. This step is important to prevent dehydration of infants who may have renal-concentrating
capacity as low as 600 mosm/L (36).
b. Upper limit of renal solute load for neonates is approximately 1,100 mosm/L (36).
3. A method for estimating potential renal solute load is given in Appendix 20, p A-22.
4. If potential renal solute load is excessive, increase water content of medical food mixture and
recalculate.
IX.
Suggested Evaluation of Nutrition Support

A. Protein Status
1. Evaluate plasma albumin concentration every 3 months until patient is 1 year old and every
6 months thereafter (Appendix 17, p A-18, for standards).
2. If plasma albumin concentration is below standard:
a. Increase prescribed amount of protein by 5% to 10% and reevaluate plasma albumin
concentration in 1 month.
b. If plasma albumin concentration remains low, repeat above process until value is in
normal range.
B. Iron Status
1. Plasma ferritin concentration.
a. Evaluate at 6, 9, and 12 months of age and every 6 months thereafter (Appendix 17,
p A-18, for standards).
b. If plasma ferritin concentration is below standard:
1) Increase iron intake to 2 mg/kg with supplements (ferrous sulfate).
2) Evaluate plasma ferritin concentration monthly in increased iron intake.
3) Continue iron supplements until plasma ferritin concentration is in normal range.
2. Complete blood count.
a. Hemoglobin and hematocrit should be evaluated at 6, 9, and 12 months of age and every
6 months thereafter (Appendix 17, p A-18, for standards).
C. Growth Status
1. Length/height and weight.
a. Measure monthly to 1 year, every 3 months to 4 years, and every 6 months thereafter.
Plot measurements on NCHS growth charts.
b. Maintain length/height and weight between 10th and 90th percentiles. Some normal
infants and children will fall above or below these percentiles. Maintain appropriate weight
for height in adults.
2. If infant's or child's length/height or weight falls below usual growth channel:
a. Increase prescribed protein and energy by 5% to 10% and remeasure in 1 month.
b. If length/height or weight remains low, repeat above process until usual growth channel is
achieved.
D. Nutrient Intake
1. Maintain records of food intake for 3 days immediately before each blood test (Appendices 24
and 25, pp A-26 and A-27).
2. Evaluate intakes of fat, linoleic and -linolenic acids, protein, energy, minerals, and vitamins
after each diet change.
a. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is
not available.
b. See Appendix 28, p A-29, for information about ordering software for diet evaluation. This
software does not calculate fatty acids.
F. Clinical Summary
1. A summary record of growth, laboratory, and nutrient intake data is useful for patient
management (Table 18-5, p 335).
X.
Sample Prescription
A. Example
Establish and fill prescription for newborn weighing 3.5 kg using Recommended Daily Nutrient
Intakes from Table 18-1, p 332, and average nutrient content from Tables 18-2 and 18-3, pp 332
and 333.
1. Establish prescription.
Energy
Fat
120 kcal/kg
420 kcal
x
x
3.5 kg
0.35
=
=
420 kcal
147 kcal
9 kcal =
16.3 g
Protein
420 kcal
0.15
63 kcal
4 kcal =
15.8 g
Carbohydrate
420 kcal
210 kcal
210 kcal
4 kcal =
52.5 g
Fluid
150 mL/kg
3.5 kg
525 mL
2. Fill prescription.
Food List
Similac With Iron Ready to Feed
ProViMin
Soy oil
Polycose Liquid
Measure
415 mL
13.7 g
2 mL
40 mL
Fat
(g)
Protein
(g)
Energy
(kcal)
16.3
0.0
1.8
0.0
5.8
10.0
0.0
0.0
282
43
16
80
18.1
15.8
421
Add water to make 525 mL (18 fl oz).

Total per day
Percentage of energy as fat
39%
Approximate osmolarity of medical food mixture is < 400 mosm/L. Estimated potential renal solute load
is < 170 mosm.
Linoleic acid is 3.49 g or 7.5% of energy; -linolenic acid is 0.36 g or 0.9% of energy.
XI.
Nutrition Support During Febrile Illness or Following Trauma

A. Rationale
1. In normal persons, febrile illness and trauma are accompanied by catabolism of body fat and
protein (47).
2. Well-nourished patients respond to infection and trauma as do normal persons.
B. Objectives of Nutrition Support

1. Maintain hydration and electrolyte balance.
a. Offer infants and toddlers Pedialyte Oral Electrolyte Maintenance Solution ad libitum
(Appendix 9, p A-9).
2. Depress catabolism
a. Enhance energy intake when possible by offering uncooked Argo cornstarch (1:2 ratio
cornstarch to fluid) ad libitum as tolerated, liquid Jell-O , Polycose powder or liquid
(Appendix 9, p A-9) added to fruit juices or Pedialyte if tolerated, and caffeine-free soft
drinks (not diet drinks).
1) 1/3 cup Polycose powder may be added to liquid Pedialyte to yield 8 fl oz.
b. Return patient to ProViMin medical food mixture and pre-illness diet as rapidly as
possible.
1) Begin with 1/2 original strength of ProViMin medical food mixture.
2) Increase to original strength as tolerated.
c. Feed Polycose solution (5-7 g/kg of carbohydrate) or carbohydrate-containing foods every
2 to 3 hours.
1) If unable to feed every 2 to 3 hours, administer solution of raw cornstarch (2-3 g/kg) to
infants older than 6 months.
2) Begin with very small amounts of raw cornstarch and gradually increase to prevent
gas, bloating and diarrhea.
d. Administer 10% glucose solution intravenously if oral intake cannot be maintained.
3. Prevent low blood glucose concentrations.
a. Add uncooked cornstarch, 2 to 3 g/kg/day to any liquids and feed every 2 to 3 hours (43).
TABLE 18-1. Recommended Daily Nutrient Intakes (Ranges) for Infants, Children, and Adults With
Pyruvate Carboxylase Deficiency
Age
Nutrient
1
Infants
0 to < 3 mo
3 to < 6 mo
6 to < 9 mo
9 to < 12 mo
Girls and Boys

1 to < 4 yr
4 to < 7 yr
7 to < 11 yr
Women
11 to < 15 yr
15 to < 19 yr
19 yr
Men
11 to < 15 yr
15 to < 19 yr
1
2
Energy1
(kcal/kg)
Fluid2
(mL/kg)
Protein
(% of energy)
Fat
(% of energy)
12 - 15
12 - 15
12 - 15
12 - 15
(% of energy)
30 - 35
30 - 35
30 - 35
30 - 35
(% of energy)
12 - 15
12 - 15
12 - 15
30 - 35
30 - 35
30 - 35
1,300 ( 900 - 1800)

1,700 (1300 - 2300)
2,400 (1650 - 3300)
900 - 1,800
1,300 - 2,300
1,650 - 3,300
12 - 15
12 - 15
12 - 15
30 - 35
30 - 35
30 - 35
2,200 (1500 - 3000)

2,100 (1200 - 3000)
2,100 (1400 - 2500)
1,500 - 3,000
1,200 - 3,000
1,400 - 2,500
12 - 15
12 - 15
12 - 15
30 - 35
30 - 35
30 - 35
2,700 (2000 - 3700)

2,800 (2100 - 3900)
2,900 (2000 - 3300)
2,000 - 3,700
2,100 - 3,900
2,000 - 3,300
120 (145 - 95)

115 (145 - 95)
110 (135 - 80)
105 (135 - 80)
(kcal/day)
150 - 125
160 - 130
145 - 125
135 - 120
(mL/day)
19 yr
Modified from reference 13.
Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL to children and adults for each
kcal ingested.
TABLE 18-2. Average Nutrient Contents of Ross Infant Formulas and Gerber Baby Foods1
Food
Measure
Cereals, dry, Ready To Serve

1 Tbsp2
Cereals, with fruit, 2nd and 3rd Foods, jarred
1 Tbsp2
2
Desserts: 2nd and 3rd Foods
1 Tbsp
2
Fruits, 1st, 2nd and 3rd Foods
1 Tbsp
Fruit, juice
1 fl oz
Meat with gravy, 2nd and 3rd Foods
1 Tbsp2
2
Vegetables: 1st, 2nd and 3rd Foods
1 Tbsp
3
Alimentum Protein Hydrolysate Formula With Iron, Ready to Feed
100 mL
3
Isomil Soy Formula With Iron, Ready to Feed
100 mL
4
Milk, skim
100 mL
ProViMin Protein-Vitamin-Mineral Formula Component With Iron
100 g
3
Similac With Iron, Ready to Feed
100 mL
1
Nutrient Values. Fremont, Michigan: Gerber Products Co, 2000.
2
US standard level measure.
3
See Appendices 4 through 7, pp A-4 to A-7, for complete nutrient composition.
4
See Appendix 8, p A-8 for complete nutrient composition.
Fat
(g)
Protein
(g)
0.17
< 0.10
< 0.04
0.00
0.00
0.67
0.04
3.74
3.70
0.19
2.00
3.65
0.25
0.16
0.11
0.09
0.07
1.58
0.20
1.86
1.66
3.53
73.00
1.40
Energy
(kcal)
15
11
12
10
16
14
6
68
68
36
312
68
TABLE 18-3. Exchange Lists for Nutrition Support of Children and Adults With Pyruvate Carboxylase
Deficiency1
Food List
Measure
Fat
(g)
Protein
(g)
Energy
(kcal)
Meat, lean
Milk, skim
Fat2
Fruit
1 oz
3
7
55
1 cup
trace
8
90
varies
5
0
45
1/2 cup canned or 1/2 cup fresh or juice
0
0
80
1/2 cup dried
0
0
60
Starch/Bread
varies
trace
3
25
Vegetable
1/2 cup cooked, or 1 cup raw
0
2
25
1
Exchange Lists for Weight Maintenance. Chicago: The American Dietetic Association, 1995.
2
Care must be taken to select fats that provide adequate linoleic and -linolenic acids, such as those high in canola or
soybean oil.
TABLE 18-4. Pyruvate Carboxylase Deficiency Diet Guide

Name:______________________________________________________________
Date: __________/_________/_________
Mo
Day
Year
Birthdate: __________/_________/__________ Age: _______________________

Mo
Day
Year
Length/Height: ____________________ (cm/in) Weight: ______________________ (kg/lb)

Medical Food
Amount
ProViMin
Protein
(g)
Fat
(g)
Energy
(kcal)
g
mL
mg
mg
mg
Skim milk
cups
Add water to make ________________________ mL ________________ (fl oz)
Beikost or table foods Tbsp/Exchanges

Cereals/Starch/Bread
Cereals: With Fruit
Desserts
Fruits/Juices
Meats
Vegetables
Total per day

Total per kg
Percentage of energy
Comments:
____________________________________________________
Nutritionist
TABLE 18-5. Pyruvate Carboxylase Deficiency Clinical Summary Sheet

Hospital Number:
Name:
Date of Birth: __________/__________/__________
Mo
Day
Year
Date
(mo/d/yr)
Physical Data
Length/
Height
(cm)
Weight
(kg)
Head
Circum
(cm)
Laboratory Data
ALA
CIT
LYS
PRO
Plasma NH3
(mol/L)
(mol/L)
(mol/L)
(mol/L)
(mol/L)
Blood
Lactate
(mmol/L)
Citrate
(mmol/L)
Nutrient Intake Data

Blood
Glucose
(mg/dL)
Ferritin
(ng/mL)
Albumn
(g/dL)
Hgb
(g/dL)
Fat
(g)
(%)
ASP
ASPNH2
(mg)
Citrate
(mg)
GLU
GLUNH2
(mg)
Protein
Energy
B1
(g)
(kcal)
(mg/day)
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PROTOCOL 18 Pyruvate Carboxylase Deficiency

Nutrition Support of Infants and Children With

Site of enzyme malfunction

Figure Q. Metabolic fates of pyruvate (modified from reference 32)

Outcome of Nutrition Support

2001 Ross Products Division